Lyme disease, now the most common tick-borne illness in the United States, has recently received much media attention, due in part to its potentially serious sequelae in untreated patients. Because a rare patient with late illness may lack antibodies to the etiologic agent, Borrelia burgdorferi, physicians may be tempted to give empiric antibiotics for illnesses that may not be Lyme disease. We have described a patient who, despite negative laboratory evidence for late Lyme disease, was treated for 3 weeks with intravenous ceftriaxone and sustained serious complications, including granulocytopenia, fever, hepatitis, and Clostridium difficile-associated diarrhea. We caution physicians to weight carefully the risks of empiric treatment for ill-defined medical problems, and to recognize the hazards of even "safe" medications.